The present invention relates to new solid forms (NSF) of phosphodiesterase type 5 inhibitors, particularly to complex crystals, which have a constant quality and which may have improved physicochemical properties such as the physical and chemical stability and a modified dissolution rate.
For the present invention, the new solid phases (NSP), are also called cocrystals and are obtained by means of technical experimentation. The cocrystals are chemical entities with physicochemical properties differing from those of the salts or polymorphs of the base active ingredient, including their salts and/or their polymorphs, due to the nature of the intermolecular interactions between the active molecule and a second solid constituent called coformer.
A cocrystal is a crystal formed by two or more non-identical molecules, in which the starting components are solid at room conditions when they are in their pure form, and wherein the two or more cocrystal components form aggregates that are characterized by being linked by intermolecular interactions—such as the Van der Waals forces, π-stacking, hydrogen bonding or electrostatic interactions—but without forming covalent bonds. By using crystal engineering techniques, a new compound with modified physicochemical properties differing from the polymorphs, salts, hydrates and/or the existing solvates, can be obtained. The adjustable screening parameters are higher, thus in the case of pharmaceutical ingredients, the physical and chemical properties of the active ingredient with clinical relevance may be optimized.
The pharmaceutical cocrystals are cocrystals containing at least one therapeutic molecule and a pharmaceutically acceptable coformer. In these crystals, their components—the active ingredient and the coformer—coexist in a well-defined stoichiometric ratio. The cocrystals in solid form tend to be more stable than the existing solvates or hydrates.
The present invention describes cocrystals which will be called “complex cocrystals”, obtained from a phosphodiesterase type 5 inhibitor—tadalafil—and a neutral coformer, where both are solids at room temperature. The obtained cocrystals have a constant quality and may have improved physicochemical properties, such as a higher solubility and dissolution rate, enhanced flow properties and enhanced stability.
The phosphodiesterase type 5 inhibitors are a group of drugs used in the treatment of erectile dysfunction and for the treatment of pulmonary arterial hypertension. Structurally, they consist of heterocycles with nitrogen atoms, aromatic groups and carbonyl groups. The phosphodiesterease type 5 inhibitors used in the clinical practice are: tadalafil, sidenafil and vardenafil. In the present invention, a method for obtaining cocrystals and other solid forms based on one of these phosphodiesterase type 5 inhibitors, e.g., tadalafil, is developed.
The tadalafil molecule, as well as other phosphodiesterase type 5 inhibitors, is structurally comprised by heterocycles, aromatic groups and carbonyl groups. Tadalafil has an indole group, a pyrazine group and a benzodioxole attached to C6 as shown in Scheme I.

In the commercial pharmaceutical preparations, tadalafil is in neutral form and consists of the D+ isomer (6R,12R), which is almost insoluble in water. The absolute bioavailability of tadalafil after its oral delivery has not been yet determined. In therapeutic concentrations, 94% of the plasmatic tadalafil is bonded to proteins, it has a half life of 17.5 hours, and is eliminated by the hepatic metabolism, predominantly as metabolites, mainly in faeces (approximately 61% of the dose) and to a lesser extent in urine (approximately 36% of the dose). Tadalafil inhibits phosphodiesterase type 5 (PDE5) and enhances the erectile function by increasing the amount of the cyclic guanosine monophosphate (cGMP). The cGMP determines the relaxation of smooth muscle and increases the blood flow in the corpora cavernosa. Its delivery is by oral route in daily doses of 5, 10 or 20 mg.
Side effects of tadalafil are usually mild or moderate, transient, and improve without medical treatment. The most frequent side effects are: headache, dyspepsia, backache, myalgia, nasal stuffiness, flushing, dizziness and limb pain.
The drugs that inhibit CYP3A4 such as ketoconazole, ritonavir, erythromycin and itriconazole increase the exposure to tadalafil, as tadalafil is the CYP3A4 substrate, and are mainly metabolized by this route. On the other hand, the drugs that induce CYP3A4 such as rifampicine, carbamazepine, phenytoin and phenobarbital may decrease tadalafil exposure. Simultaneous delivery of an antacid such as aluminum hydroxide/magnesium hydroxide slows the tadalafil absorption rate. A substantial alcohol consumption (more than 5 units) in combination with tadalafil may increase the risk of orthostatic signs and symptoms, including increased heart rate, decreased blood pressure on standing, dizziness and headaches. When tadalafil is administered jointly with alpha-blocking agents such as tamsulosine, doxazosine or other anti-hypertensive agents such as amlodipine, metoprolol, bendrofluazide, enalapril or angiotensin II blockers, they may mutually enhance, in greater or lesser extent, its hypotensive effect.
Document US20090131667A1, describes the obtention and the process for manufacturing an amorphous form of tadalafil by assisted evaporation, with distillation of a tadalafil solution in an organic solvent. It also describes the obtention and the process for manufacturing the pure crystalline form B of tadalafil by precipitation of a tadalafil solution in a ketone solvent; and describes the preparation of a mixture of tadalafil form A and form B by precipitation of a tadalafil solution in an ester solvent.
Document US2006/0111571A1 (MX/a/2007/003719), describes the obtention and the process for making crystalline forms (polymorphs) I, II, III, IV, V, VI, VII and VIII of tadalafil by crystallization and/or precipitation in organic solvents; it describes the method of preparing the crystalline tadalafil form I by crystallizing tadalafil solutions in organic solvents such as 2-methoxyethanol, ethanol, acetonitrile, 1-propanol, isopropanol, ethyl acetate, toluene, dimethyl sulfoxide, n-butanol, methanol, chloroform, tetrahydrofuran, acetone and/or methyl ethyl ketone, and by precipitation when combining these solutions with solvents such as petroleum ether, cyclohexane, toluene, xylene, benzene and methyl-tert-butyl-ether, until obtaining a precipitate which was isolated. It describes the method for obtaining the crystalline form I starting from crystalline forms II, III and IV under certain humidity and temperature conditions; it describes the method for obtaining the crystalline form II from the crystallization of a tadalafil solution in acetone or methyl ethyl ketone or by precipitation adding a solvent such as petroleum ether, cyclohexane or methyl tert-butyl ether, to the methylethyl ketone solution; it describes the method for obtaining the crystalline form III of tadalafil, starting from the crystalline form II by heating at 65° C.; it describes the method for preparing the crystalline form IV, by crystallizing a tadalafil solution in methylene chloride or by precipitation from this solution with the addition of petroleum ether; it describes the method for obtaining of the crystalline form V from an acetic acid solution; it describes the obtention of the crystalline form VI using form IV by slurry in methanol and drying at 65° C.; it describes the obtention of tadalafil form VII using forms II, IV and V by slurry in toluene and drying at 65° C.; it describes the method for preparing the crystalline form VIII from the crystalline form IV in a range of 50-70° C.
The present invention, unlike the crystals cited in documents US20090131667A1 and US20060111571A1, comprises “complex” cocrystals which are obtained from a phosphodiesterase type 5 inhibitor such as tadalafil, using its polymorph I. The cocrystals of the present invention are obtained with coformers such as 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid, D-malic acid and L-tartaric acid. These coformers have one or more hydroxyl and carboxyl groups, forming an aggregate by hydrogen bonding and van der Waals interactions with tadalafil or other active ingredients that have structural similarities, such as sildenafil and vardenafil.
The application WO20120099323 describes the formation of tadalafil cocrystals with oxalic acid, salicylic acid, 4-hydroxybenzoic acid, malonic acid, 3-phenylpropanoic acid, methylparaben and propylparaben. Document Weyna et al., “Crystal engineering of multiple-component organic solids: Pharmaceutical cocrystals of tadalafil with persistent hydrogen bonding motifs”, CrystEngComm, 2012. 14, 2377 describes the synthesis of tadalafil cocrystals with methylparaben, propylparaben, cinnamic acid and 4-hydroxybenzoic acid.
Although it is true that documents WO20120099323 and the Weyna et al. article describe the existence of tadalafil cocrystals, and even when during the process of obtaining cocrystals one may envisage a great amount of combinations with the possible coformers, not all the combinations produce a cocrystal or a stable solid form, as shown in the specification of the present application.
The present invention comprises new solid phases of tadalafil which may show enhanced physicochemical properties, such as a enhanced solubility, dissolution rate, bioavailability, stability and/or flow properties.